Response to Treatment of Infection Due to Mycobacterium avium Complex with Trimethoprim-Sulfamethoxazole

New 2,4-Diamino-5-(2‘,5‘-substituted benzyl)pyrimidines as Potential Drugs against Opportunistic Infections of AIDS and Other Immune Disorders. Synthesis and Species-Dependent Antifolate Activity

“…Its activity against human isolates of intact M. avium in culture, as well as that of the other new compounds reported in this paper, was lower than that of the previously synthesized analogues with a simple ω-carboxyalkyloxy, ω-carboxyalkynyl, or ω-carboxyalkyl substituent at the 5′-position, suggesting less efficient cell penetration by compounds with bulkier 5′-substituents containing an extra phenyl ring. However, two of the previously synthesized 5′-(ω-carboxyalkyloxy) and 5′-(ω-carboxyalkynyl) analogues (12,13,16) were active at a physiologically realistic concentration of 2 µg/mL (ca. 5000 nM).…”

“…Interestingly, trimethoprim by itself is reported to be ineffective against human isolates of M. avium even at a concentration of up to 1.5 µg/mL, 15 although there is at least one report that it is clinically effective against M. avium infection when combined with sulfamethoxazole. 16 It may be noted that, while their in vitro molar equivalent potency is considerably lower than that of several popular macrolide and quinolone antibiotics, 13,17,18 the antifolate activity of 12, 13, and 16 would probably not be affected by macrolide resistance, an emergent problem in the clinical management of M. avium infection. 19 Thus, when used as a twodrug combination, or even as a three-drug combination with a sulfa drug like dapsone, 20,21 these compounds may be able to extend the usefulness of macrolides in the treatment of this disease.…”

“…Since 2 μg/mL is generally considered a physiologically achievable concentration, these compounds could have therapeutic utility in the treatment of disseminated M. avium infection. Interestingly, trimethoprim by itself is reported to be ineffective against human isolates of M. avium even at a concentration of up to 1.5 μg/mL, although there is at least one report that it is clinically effective against M. avium infection when combined with sulfamethoxazole . It may be noted that, while their in vitro molar equivalent potency is considerably lower than that of several popular macrolide and quinolone antibiotics, ,, the antifolate activity of 12 , 13 , and 16 would probably not be affected by macrolide resistance, an emergent problem in the clinical management of M. avium infection .…”

“…Like trimethoprim, the compounds that provided the impetus for the present work were 2,4-diamino-5-(substituted benzyl)pyrimidines; however, as with piritrexim but in contrast to trimethoprim, the benzyl group was 2′,5′-disubstituted rather than 3′,4′,5′-trisubstituted. Furthermore, while the 2′-methoxy group of piritrexim was retained, the 5′-substituent consisted of either a hydrophobic long-chain alkoxy group (3)(4)(5)(6)(7) or various water-solubilizing ω-carboxyalkoxy (8)(9)(10)(11)(12)(13), ω-carboxyalkynyl (14)(15)(16), ω-carboxyalkyl (17)(18)(19), carboxybenzyloxy (20,21), or carboxyphenoxypropynyl (22,23) groups. The structures of trimethoprim and 2,4-diamino-5-(2′,5′-substituted benzyl)pyrimidines 2-23 are shown in Figure 1.…”